This project will investigate the signaling mechanisms that control non-small cell lung carcinoma (NSCLC) cell growth and resistance to therapy, and will explore the anti- cancer effects of novel strategies designed to modulate these signals. It addresses this area by focusing on the growth promoting signaling mechanisms triggered in NSCLC by aberrant extracellular matrices deposited in the lung. It is generally well-accepted that tumor cells interact with their surrounding matrix and that this and related host factors contribute to carcinoma development and progression. Unfortunately, this idea has not translated into clinically useful strategies for the management of lung cancer. This project will test the hypothesis that host cell- and tumor cell-derived fibronectin, a matrix molecule highly expressed in tobacco-related lung disease, is an important factor that stimulates NSCLC cell growth and survival through signals related to the mTOR pathway that are elicited by activation of the integrin a51. This hypothesis is supported by our own work showing that exposure to tobacco-related products stimulates fibronectin expression in lung fibroblasts both in vitro and in vivo, and that fibronectin stimulates the growth of NSCLC by triggering a51 integrin receptor-mediated signals that appear mediated via mTOR. Fibronectin also inhibits NSCLC apoptosis induced by chemotherapeutic agents. Interestingly, the relative expression of fibronectin isoforms seems to play a role in tumor proliferation. Finally, we have generated data in vivo showing that strategies able to affect fibronectin expression or recognition and mTOR signaling inhibit tumor progression. These data suggest that an altered lung matrix characterized by a relative increase in fibronectin content stimulates NSCLC proliferation. This hypothesis will be tested in specific aims designed to: 1) determine the role of Akt/mTOR/S6K1 related pathways in fibronectin-induced proliferation/survival and chemotherapy-induced apoptosis of NSCLC and 2) examine the role of fibronectin, 1521, and the Akt/TOR/S6K1 pathway in NSCLC using the K-ras and Lewis Lung Carcinoma models of lung cancer. Project Narrative: This project will investigate how alterations in the connective tissue matrix of the lung promotes lung cancer progression and how agents that affect the lung matrix may inhibit this process.